Brain Imaging: Tackling Chronic Traumatic Encephalopathy

Posted on April 21, 2015 by Dr. Francis Collins

Caption: Left to right, brain PET scans of healthy control; former NFL player with suspected chronic traumatic encephalopathy (CTE); and person with Alzheimer’s disease (AD). Areas with highest levels of abnormal tau protein appear red/yellow; medium, green; and lowest, blue.
Credit: Adapted from Barrio et al., PNAS

If you follow the National Football League (NFL), you may have heard some former players describe their struggles with a type of traumatic brain injury called chronic traumatic encephalopathy (CTE). Known to be associated with repeated, hard blows to the head, this neurodegenerative disorder can diminish the ability to think critically, slow motor skills, and lead to volatile, even suicidal, mood swings. What’s doubly frustrating to both patients and physicians is that CTE has only been possible to diagnose conclusively after death (via autopsy) because it’s indistinguishable from many other brain conditions with current imaging methods.

But help might be starting to move out of the backfield toward the goal line of more accurate diagnosis. In findings published in the journal PNAS [1], NIH-supported scientists from the University of California, Los Angeles (UCLA) and the University of Chicago report they’ve made some progress toward imaging CTE in living people. Following up on their preliminary work published in 2013 [2], the researchers used a specially developed radioactive tracer that lights up a neural protein, called tau, known to deposit in certain areas of the brain in individuals with CTE. They used this approach on PET scans of the brains of 14 former NFL players suspected of having CTE, generating maps of tau distribution throughout various regions of the brain.

Although CTE has become almost synonymous with the gridiron, the condition can be an issue in other contact sports, including soccer, ice hockey, lacrosse, and boxing. It’s also a potential problem for people with histories of car crashes, exposure to explosions during combat, or head injuries during seizures.

We’re still learning about the short and long term consequences of blows to the head. Current medical technologies can’t detect structural damage to the brain following a concussion, even in people with clear cognitive dysfunction, balance problems, dizziness, or loss of consciousness. Although these symptoms often resolve relatively quickly, some people battle persistent symptoms that last weeks or months. It’s thought that repeated concussions eventually will stress brain cells. The end result: abnormal tangles of tau protein that accumulate in neurons.

If this sounds familiar, it may be because tau tangles also are associated with Alzheimer’s disease. However, CTE isn’t Alzheimer’s disease. CTE’s tau tangles arise in the brains of much younger people and tend to appear first in regions of the brain that aren’t typically affected by Alzheimer’s disease. In addition, although CTE can cause dementia, it’s not clear whether the condition leads to dementia in all cases.

Much work remains to be done to find and delineate possible differences in the locations of tautangles in the brains of living people with CTE and with Alzheimer’s disease. In the current study, researchers, led by UCLA’s Jorge Barrio, assembled three groups: 14 former NFL players with various degrees of suspected CTE, 24 people who met standard diagnostic criteria for Alzheimer’s disease, and 28 cognitively normal people. All participants were given an intravenous injection of a radioactive compound, called [F-18] FDDNP, designed to travel through the bloodstream and into the brain. Once there, the tracer apparently attaches to tau proteins, which then can be detected on a PET scanner. From start to finish, the process takes roughly an hour.

By analyzing the PET scans, Barrio and colleagues identified four distinctive patterns of tau tangles in brains of the former football players that didn’t appear in the brains of normal controls. Researchers said these patterns appear to parallel the damage that occurs from a concussion, starting in the midbrain; advancing outwards to subcortical areas and the amygdala—a region of the brain that controls anxiety and response to stress; and finally moving into the cerebral cortex. They also found that locations of the four tau patterns by PET scan were generally consistent with brain tissue pathology reports from autopsies of several athletes with confirmed CTE, though the prominence of the signal in the midbrain was unexpected.

Next, the team compared the brain scans of the football players with suspected CTE to those of Alzheimer’s disease patients. According to the researchers, the scans showed that, in contrast to what they observed in the brains of football players, the tau tangles in Alzheimer’s disease appeared to start—not end—in the cerebral cortex.

This area of imaging research provides hope that, with additional study, health-care professionals may be able to diagnose CTE in people while they are alive. However, exactly what should be used as the basis for such analyses remains an area of intense scientific debate. For example, in contrast to what Barrio’s group found, a panel of experts convened by NIH’s National Institute of Neurological Disorders and Stroke (NINDS) recently concluded that the pathological signature of CTE resides in the cerebral cortex [3].

There’s also been some controversy on another front. A recent New York Times article [4] reported that Barrio and his UCLA colleague Gary Small used their FDDNP tau tracer to scan, for a fee, several former NFL players with suspected CTE. These tests led to a warning from the Food and Drug Administration because FDDNP has not been approved for any clinical use, including diagnosis of CTE.

The good news for people suffering from traumatic brain injuries is that a great many research groups are working on developing tau tracers for imaging CTE and other neurodegenerative disorders. So, there should soon be more definitive answers regarding diagnosis. Meanwhile, NINDS is also looking to support the sort of larger studies needed to characterize CTE more precisely, thereby providing clinicians with better tools to identify and help individuals affected by each stage of this disease.

References:

[ 1] In vivo characterization of chronic traumatic encephalopathy using [F-18] FDDNP PET brain imaging. Barrio JR, Small GW, Wong KP, Huang SC, Liu J, Merrill DA, Giza CC, Fitzsimmons RP, Omalu B, Bailes J, Kepe V. Proc. Natl. Acad Sci USA. 2015 Apr 6. pii: 201409952. [Epub ahead of print]

[2] PET scanning of brain tau in retired national football league players: preliminary findings. Small GW, Kepe V, Bailes J, Barrio JR et al., Am J Geriatr Psychiatry 21(2):138-144.

[3] Report from the First NIH Consensus Conference to Define the Neuropathological Criteria for the Diagnosis of Chronic Traumatic Encephalopathy (National Institute of Neurological Disorders and Stroke/NIH)

[4] F. D. A. warns researchers on claims of drug to detect brain disease, Belson B. New York Times, April 11, 2015.

Links:

Sports and Health Research Program (Foundation for the National Institutes of Health)

Heads Up to High School Sports (Centers for Disease Control and Prevention)

Jorge Barrio Lab (UCLA)

NIH Support: National Institute on Aging; National Center for Advancing Translational Sciences